Clinical assessment of Optivate®, a high‐purity concentrate of factor VIII with von Willebrand factor,in the management of patients with haemophilia A

Summary. Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor‐screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high‐purity FVIII product with von Willebrand factor, Optivate^®. Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long‐term studies. Seventy previously treated patients with severe haemophilia A, with ≥20 exposure days, were recruited into two long‐term, multicentre, open‐label studies. The protocols were virtually identical. Patients received Optivate^® either prophylactically or on‐demand. A mean of 159.0 EDs were experienced over 11 320 infusions. Under both conditions, Optivate^® was well tolerated. Only 10% of patients experienced a treatment‐related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on‐demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on‐demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate^® in both prophylactic and on‐demand management of patients with haemophilia A.     

The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A

BACKGROUND: B-domain-deleted recombinant factor VIII (BDDrFVIII) was developed when the B-domain was found to be redundant for maintaining haemostasis. This allows formulation of the final product without albumin added as a stabilizer. METHODS: Three multicentre clinical studies and one pharmacokinetic study were conducted in 218 patients to evaluate the safety and haemostatic efficacy of BDDrFVIII. RESULTS: Previously treated patients (n = 113; median duration, 1711 days; median exposure days, 385; total 98,096,287 IU infused) rated 97-99% of all infusions as good or excellent efficacy. FVIII inhibitor was noted in one patient in the previously treated patient cohort after 113 exposure days. Among 101 previously untreated patients, responses to BDDrFVIII were rated as excellent or good in 92-95% of infusions (median duration, 1413 days; median exposure days, 148; total 12,636,458 IU infused). Thirty-two previously untreated patients developed inhibitors after a median duration of 12 exposure days (range, 3-49). Sixteen of 32 (50%) patients had low levels (< or = 5 Bethesda units) and 16 had high levels of inhibitors. Inhibitors disappeared in six of 14 (43%) of the high-level and six of eight (75%) of the low-level patients who underwent immune tolerance induction therapy. A total of 42 patients underwent surgery and the overall efficacy of BDDrFVIII was rated as excellent or good for 99.6% of infusions. CONCLUSIONS: The results of these clinical studies indicate that BBDrFVIII is safe and effective and has haemostatic activity similar to that of full-length FVIII concentrates.     

Pharmacokinetics of Optivate®, a high‐purity concentrate of factor VIII with von Willebrand factor,in patients with severe haemophilia A

Summary. Optivate^® is a high purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate, which is manufactured using two antiviral processes: solvent/detergent and terminal dry heating (80°C for 72 h). A multicentre, non‐randomized open‐label study in 15 patients was conducted to test the pharmacokinetics (PK) of Optivate^®. PK variables were analysed for the patients’ prior FVIII product (PK1), their first dose of Optivate^® (PK2) and at 3 months therapy (PK3). Mean non‐compartmental half‐lives (h) were 14.1, 12.4 and 12.1, respectively (P = 0.45), mean clearances (mL h^?1 kg^?1) were 3.6, 3.2 and 3.1, respectively (P = 0.051), MRTs (h) were 19.0, 17.3 and 17.4, respectively (P = 0.39) and mean AUC_0–48h (h IU mL^?1) were 14.3, 15.4 and 16.6, respectively (P = 0.051) and mean AUC_0–∞ (h IU mL^?1) were 15.9, 16.4 and 17.9, respectively (P = 0.18). The recovery data from this PK study was aggregated with recovery data collected from another study, with similar design but devoid of the other PK measurements. A total of 309 recoveries were conducted in 70 patients. The overall mean recovery per subject across 27 Optivate^® batches was 2.7 IU dL^?1 per IU kg^?1. There were no clinical differences between Optivate^® and other FVIII products, and except for volume of distribution (Vd), no statistically significant differences were seen with respect to any of the other PK variables, or in recovery between weeks 0 and 12. Therefore, the PK of FVIII is not affected by the processes used to manufacture Optivate^®, which can be expected to be effective in the management of patients with haemophilia A.     

Safety and efficacy of a plasma-derived monoclonal purified factor VIII concentrate during 10 years of follow-up

In 1995, AAFACT, a new monoclonal purified factor VIII concentrate (FVIII), derived from human plasma, was introduced in the Netherlands. The monoclonal purification based production process includes a viral inactivation step by solvent/detergent treatment. Products manufactured according to this procedure, for example Hemofil M are used worldwide. The aim of the present study was to assess inhibitor development in a large cohort of previously treated patients (PTPs) who were followed up for 10 years. In addition, efficacy, HIV and hepatitis C virus (HCV) transmission, and allergic reactions were monitored. All 165 patients with severe haemophilia A (FVIII<1%) known at the van Creveldkliniek who ever used AAFACT during the period from October 1995 to September 2005 were included. Two of them were previously untreated patients (PUPs) and two others had <50 exposure days. Data on FVIII consumption, number of exposures, bleedings and hospitalization days were collected from start of AAFACT until last clinical and laboratory evaluation while on this product. At the end of follow-up, 91 patients were still using this plasma-derived FVIII. Median age at start of follow-up was 26 years (range 1-52). None of the patients reported lack of efficacy. Median FVIII consumption per patient during follow-up was 2058 IU kg(-1) bodyweight per year, and median number of exposures was 148 per year. During 1029 patient-years of follow-up, one inhibitor was diagnosed in a previously treated patient PTP. This patient developed high titre inhibitor following surgery for which he, during 1 week, had been treated with continuous infusion with recombinant FVIII. No inhibitor occurred during 68 cases of surgery using continuous infusion with AAFACT. No viral transmissions or other adverse events occurred during 10 years of follow-up; AAFACT appeared to be an effective and safe FVIII product.     

Low incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A treated with octanate®: Final report from a prospective study

Introduction

Octanate^® is a human, plasma‐derived, von Willebrand factor‐stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A.

Aim

This prospective, open‐label study aimed to assess the immunogenicity of octanate^® in previously untreated patients (PUPs).

Methods

The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate^® for the prevention and treatment of bleeds and in surgical procedures were also assessed.

Results

Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate^® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on‐demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as “excellent” in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated “very good” in 99.9% of infusions.

Conclusion

In PUPs with severe haemophilia A, octanate^® demonstrated haemostatic efficacy with a low rate of inhibitor development.     

Clinical efficacy, safety and pharmacokinetic properties of the factor VIII concentrate Haemoctin® SDH in previously treated patients with severe haemophilia A

Clinical efficacy, safety and pharmacokinetic properties of the high-purity double-virus inactivated plasma-derived factor VIII concentrate Haemoctin SDH (pdFVIII) were evaluated in three prospective open-label uncontrolled studies in previously treated patients (PTPs) with severe haemophilia A. The pharmacokinetic properties assessed at baseline and after 3 months of treatment are in accurate accordance with published data and remain unchanged over time (study A, n = 12). Mean terminal elimination half-life was 11.8 and 11.9 h, mean incremental recovery (IU dL(-1)/IU kg(-1)) was 2.3 and 2.0, respectively. Long-term efficacy and safety, in particular the potential immunogenicity, were investigated in a total of 53 PTPs (studies A and B) treated prophylactically and on-demand, as required. PdFVIII has shown to be effective in preventing and controlling bleeding episodes; 23.5% of patients were free of bleeding events. A total of 177 haemorrhages occurred with 74.0% resolving after a single infusion, 87.6% within two infusions. 98.3% of responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy has been demonstrated in 10 surgical procedures including general and severe orthopaedic interventions (study C). No complication occurred in any surgery. Few adverse events were reported, one patient developed a high-titre FVIII inhibitor without clinical relevance. In all three studies, over 6 million units were administered in nearly 4300 infusions, approximately 94% units or infusions were given for prophylaxis and only 6% for treatment on-demand. In conclusion, pdFVIII has shown to be effective, safe and well tolerated in long-term prophylaxis and treatment on-demand as well as after minor and major surgical procedures.     

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A

Summary. OBI‐1 is a recombinant B‐domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti‐FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI‐1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI‐1 in a double‐blind fashion. FVIII levels were assayed using both a one‐stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti‐porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C_max appeared higher for OBI‐1 (OSCA: 176.00 U dL^?1, standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL^?1) than Hyate:C (OSCA: 82.3 ± 19.22 U dL^?1; chromogenic: 52.67 ± 13.8 U dL^?1). Mean AUC also appeared higher for OBI‐1 (OSCA: 2082.87 ± 1323.43 U h^?1dL^?1; chromogenic: 1817.28 ± 625.14 U h^?1dL^?1) than Hyate:C (OSCA: 1177.8 ± 469.49 U h^?1dL^?1; chromogenic: 707.61 ± 420.05 U h^?1dL^?1). Two infusion‐related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti‐porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI‐1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti‐porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.     

Clinical experience with Optivate®, high‐purity factor VIII (FVIII) product with von Willebrand factor (VWF) in young children with haemophilia A

Summary. Optivate^® is a high‐purity FVIII/VWF product. Its safety, tolerability and efficacy in subjects ≥12 years have been demonstrated. This study was undertaken to assess Optivate^® in children with haemophilia A. Twenty‐five children, including one PUP (previously untreated patient), aged 1–6 years (mean 4.67 years) were treated with Optivate^® for 26 weeks. Inhibitors were assessed every 3 months and viral status at the study start and end. Prophylaxis was used by five boys and on demand by twenty. The mean number of bleeds in the study was lower compared to the same period pre‐study (12.0/child vs. 16.2/child), with fewer bleeds (P < 0.05) in the prophylactic subgroup (8.0/child) compared with the on‐demand sub‐group (13.4/child). Fourteen major bleeds were reported, all by the on‐demand sub‐group. Children on prophylaxis were administered a mean of 59.4 infusions; on‐demand group 35.1 infusions. A total of 998 infusions were used with a mean dose of 29.1 IU kg^?1, and a mean of 38.6 exposure days (ED). Children <4 years used higher doses, and reported fewer bleeds than older children. Children’s Parents/Guardians rated Optivate^® as helpful or very helpful in controlling 97.5% of bleeds by the prophylactic group, and in 98.5% of the bleeds in the on‐demand group. Only 5 of 101 ADRs were treatment‐related events (5%), all were mild and non‐serious. There were no clinically significant changes in vital signs, viral transmissions or inhibitors. In young children Optivate^® was well tolerated, safe and efficacious.     

Efficacy, safety and tolerability of recombinant factor VIII (REFACTO®) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years. Most patients (188/217; 86.6%) had severe to moderately severe haemophilia A, of whom 153 completed sufficient diary information for the main efficacy analysis. These 153 patients experienced a median of 6.6 (interquartile range 1.4-18.6) bleeding episodes per year. Patients treated with prophylaxis experienced a median of 4.4 (1.1-9.3) bleeds per year, while patients treated on-demand experienced a median of 22.8 (11.3-29.0) bleeds per year. Overall, most physicians (41/43 [95.3%]) were 'very satisfied' or 'satisfied' with the efficacy of REFACTO in the treatment of bleeding episodes. A total of 137 non-serious adverse events have been reported in 52/217 patients (24.0%) to date. In addition, 129 serious adverse events in 87 patients (40%) were reported, including 41 cases of 'less than expected therapeutic effect' (LETE). Of these, 39 LETE cases were reported in one centre; however, patients in this centre experienced considerably fewer bleeding episodes per year than patients outside this centre. Overall, six patients (2.8%) have developed de novo inhibitors, three of which were considered high titre. Four of these patients were at high risk (0-50 exposure days [ED]) of inhibitor formation, one was at intermediate risk (51-100 ED) and one was at low risk (>100 ED). These results emphasize the benefit of postmarketing surveillance and, overall, this study confirms the efficacy, safety and tolerability of REFACTO in the treatment of patients with haemophilia A.     

Effect of factor VIII concentrate on leucocyte cytokine production: characterization of TGF-beta as an immunomodulatory component in plasma-derived factor VIII concentrate

Clinical and subclinical immunological abnormalities have been reported in HIV-seronegative haemophiliacs. The mechanisms by which these abnormalities arise remain unclear. As cytokines are important biological response modifiers, the effect of a FVIII concentrate on production of a range of cytokines, by a variety of cells, was investigated. A whole blood technique was used and the in vitro modulation of cytokine synthesis by an intermediate-purity plasma-derived factor VIII (pdFVIII) concentrate was analysed using multiparameter flow cytometry. In cell cultures exposed to pdFVIII, T cells showed reduced production of TNF-alpha, IL-2 and IFN-gamma; monocytes showed reduced production of TNF-alpha, IL-1alpha, IL-1beta, IL-6, IL-8 and IL-12 but an increase in IL-10 synthesis; IFN-gamma synthesis by NK cells was reduced. All changes in cytokine synthesis and the reduction in cell surface expression of CD69, a signal transduction molecule contributing to both cytokine and cytokine receptor synthesis, were in a dose-dependent manner in cultures exposed to FVIII concentrate. These changes were characteristic of TGF-beta. Addition of anti-TGF-beta to FVIII reduced these changes in T-cell cytokine production, suggesting TGF-beta may be an important immunomodulatory agent in the pdFVIII concentrate. The Th2 cytokine bias shown in the presence of pdFVIII concentrate, in vitro, may explain the increase in rates of certain types of infections reported in these patients, which require Th1 cytokine production for an effective response.     

Laboratory and clinical markers of HIV infection in a national haemophilia cohort treated with recombinant factor VIII concentrate

Over an interval of approximately six months beginning in October 1993, most haemophilia A patients in Canada were switched from a plasma-derived intermediate-purity factor VIII concentrate (ipVIII) to a recombinant factor VIII (rVIII). In order to determine the consequence of this change in therapy on progression of HIV infection, we gathered surveillance data on clinical status and CD4 and CD8 cell counts in those patients who were HIV seropositive at the time of switching concentrates. Data were recorded at the time of switchover, annually for 2 years thereafter, and retrospectively at a point 1 year prior to the switch. CD4 cells fell significantly over the study period. Multiple direct comparisons revealed that this decline was restricted to the time intervals which included the final year in which patients received intermediate-purity factor VIII concentrate (ipVIII). In the 2 year interval in which rVIII was used exclusively, there was a nonsignificant fall in CD4 cells. Changes in CD4 cells did not correlate with the intensity of exposure to either ipVIII or rVIII. CD8 cells did not fall significantly over the study period. There was no obvious reduction in the incidence of death or clinical progression over the 2 years in which rVIII was used. However, we are hopeful that the stabilizing trend in CD4 cell counts which followed the introduction of rVIII will be predictive of corresponding clinical stabilization over the coming years.     

Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A.

The efficacy and safety of an advanced category recombinant antihaemophilic factor produced by a plasma- and albumin-free method (rAHF-PFM) was studied in 111 previously treated subjects with haemophilia A. The study comprised a randomized, double-blinded, crossover pharmacokinetic comparison of rAHF-PFM and RECOMBINATE rAHF (R-FVIII); prophylaxis (three to four times per week with 25-40 IU kg(-1) rAHF-PFM) for at least 75 exposure days; and treatment of episodic haemorrhagic events. Median age was 18 years, 96% of subjects had baseline factor VIII <1%, and 108 received study drug. Bioequivalence, based on area under the plasma concentration vs. time curve and adjusted in vivo recovery, was demonstrated for rAHF-PFM and R-FVIII. Mean (+/-SD) half-life for rAHF-PFM was 12.0 +/- 4.3 h. Among 510 bleeding events, 473 (93%) were managed with one or two infusions of rAHF-PFM and 439 (86%) had efficacy ratings of excellent or good. Subjects who were less adherent to the prophylactic regimen had a higher bleeding rate (9.9 episodes subject(-1) year(-1)) than subjects who were more adherent (4.4 episodes subject(-1) year(-1); P < 0.03). One subject developed a low titre, non-persistent inhibitor (2.0 BU) after 26 exposure days. These data demonstrate that rAHF-PFM is bioequivalent to R-FVIII, and suggest that rAHF-PFM is efficacious and safe, without increased immunogenicity, for the treatment of haemophilia A.     

A post-marketing safety and efficacy assessment of a monoclonal antibody purified high-purity factor VIII concentrate

Summary. The identification of infrequent side-effects of clotting factor concentrates, undetected by clinical trials, is facilitated by post-marketing surveillance. We present a post-marketing surveillance study in which 97 patients with haemophilia A, attending three haemophilia centres, were treated over a median follow-up period of 284 days (range 1–1074), and a total follow-up period of 30,080 days, with a pasteurized immunoaffinity purified factor VIII concentrate (Monoclate-P, Armour, Collegeville, USA). 5216 infusions, using 10,527,000 units of Monoclate-P, were carried out, mostly for routine haemarthroses or prophylaxis.
No new inhibitors were observed during the study. At the start of the study 60/97 were HIV seropositive, 67/97 HBs antibody positive, 12 HbsAb negative and the remainder HBsAb positive before the study period. 13/14 tested were HAV seropositive at the beginning of the study. One patient became HAV seropositive during the study period, an infection thought to be community acquired. No other seroconversions were observed. Only one mild transfusion reaction was observed. This study confirms the safety and efficacy of Monoclate-P. Post-marketing surveillance or nationally organized pharmaco-vigilance should be practiced more widely to enable identification of low-frequency side-effects of treatment.     

Clinical observation on safety and efficacy of a plasma‐ and albumin‐free recombinant factor VIII for on‐demand treatment of Chinese patients with haemophilia A

Summary. Recombinant FVIII (rFVIII) has become the best choice for treating bleeding of haemophilia A patients. A plasma‐ and albumin‐free recombinant FVIII (rAHF‐PFM, ADVATE^®), as the third generation rFVIII, virtually eliminates the risk of blood‐borne disease transmission by excluding all human blood derived additives throughout cell culture, purification and formulation. In this multicentre prospective clinical study we evaluated the efficacy, safety and immunogenicity of ADVATE^® in Chinese patients with haemophilia A. Fifty‐eight patients enrolled and received ADVATE^® treatment. Of the patients enrolled, eight (13.79%) had severe haemophilia, 45 (77.59%) had moderate haemophilia and five (8.62%) had mild haemophilia. Fifty‐four patients completed 6 months of observation. A total of 781 bleeds occurred in these 58 subjects, all evaluable per‐protocol. A total of 984 infusions were administered with a mean of 17.0 ± 11.1 infusions per patient. On average, each patient received a mean of 15030.2 ± 7972.7 IU ADVATE^® (median 13 625 IU, range 9500–19 750 IU) during 6 months. The majority of bleeding episodes (95.9%) were successfully treated with one or two infusions of ADVATE^®. Overall, response to the first ADVATE^® treatment was rated as either ‘excellent’ (82.8%) or ‘improved’ (17.2%) in all subjects. All patients tolerated ADVATE^® infusions well. One patient (1/58, 1.7%) developed an inhibitor of 4 Betheseda units at day 180 visit. The results of this clinical observational study support that ADVATE^® is efficacious, safe and well tolerated in the treatment of Chinese patients with haemophilia A.     

Spectrum of factor VIII mutations in Arab patients with severe haemophilia A

Summary.  Haemophilia A is an X-linked recessive bleeding disorder caused by mutations in the factor VIII (FVIII) gene. The mutation spectrum is known in various populations, but not in Arabs. We selected 20 unrelated Arab patients with severe haemophilia A. Those patients underwent detailed clinical examination and their plasma FVIII:C activity was also measured. We extracted DNA from their blood samples and we looked for intron 22 inversion, deletions, insertions and base substitutions in the FVIII gene. Intron 22 inversion was common (detected in 11 patients, 55%), eight base substitutions (six of which are novel) were detected in nine patients (45%) and none had an insertion or deletion. Of eight base substitutions detected, six were potentially pathologic and this was correlated well with the severe clinical phenotype observed. Larger studies with more Arab patients from various Arab countries are needed in order to establish a solid conclusion about the prevalence of various mutations in this unique ethnic group. For the families included in this study, the results obtained can be helpful for carrier testing, prenatal diagnosis or pre-implantation techniques for detection of unaffected embryos.     

Persistent factor VIII inhibitors and orthopaedic complications in children with severe haemophilia A

Summary. Persistence of inhibitors against factor VIII (FVIII) may be a risk factor that increases physical disability in haemophilia A (HA) patients. This study aimed to evaluate prevalence of FVIII inhibitors in previously treated children with severe HA and the impact of persistent inhibitors on knee joint status and lumbar bone mineral density (BMD). Fifty children with severe HA, FVIII <1%; aged 5–16 years were enrolled in this study; they received plasma‐derived FVIII on‐demand treatment for 50–250 exposure days (EDs). Inhibitors were checked at basal visit and were followed up for 1 year, using Bethesda assay. Cross‐sectional clinical scoring and radiological evaluation of the knee joint (by Arnold‐Hilgartner staging and Pettersson score), along with lumbar BMD by Dual Energy X‐ray Absorptiometry (DEXA) were performed. Patients with persistent inhibitors for 1 to 5 years, median 2.5 years, were 10 (20%). Six had high titre and none of them had completely normal knees, seven had advanced knee arthropathy and six had low lumbar BMD in comparison to 2 and 8 of the 40 patients without inhibitors respectively (P < 0.05). Persistence of inhibitors for more than 2 years without immuno‐prophylaxis was a risk factor for joint damage. Low lumbar BMD was found in 88.9% of patients with stages four and five knee arthropathy and in 66.7% of patients with positive hepatitis C. Severe HA children in this Egyptian study had a relatively low prevalence of persistent FVIII inhibitors, which, if not treated, may increase the risk of knee arthropathy and lumbar osteopenia.     

von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients

We investigated the neutralization activity of factor VIII (FVIII) antibodies of 12 haemophilia A patients, acquired during treatment with plasma-derived FVIII concentrates. All plasma samples, drawn in a clinically stable situation before any immunotolerance treatment, contained anti-A2 domain and anti-light-chain FVIII antibodies. In nine patients' plasmas, containing relatively high amounts of FVIII light-chain antibodies (53-96%), a higher neutralization activity was found against recombinant FVIII concentrate (Recombinate) than against plasma-derived von Willebrand factor (vWF)-containing concentrate (Haemoctin SDH). No difference in neutralization of the two concentrates was found in two patients' plasmas with almost equal content of FVIII light- and heavy-chain antibodies, or one plasma with predominantly heavy-chain antibodies. These results suggest that haemophilia A patients with relatively high amounts of FVIII light-chain antibodies in plasma might benefit by infusion of FVIII concentrates containing vWF because vWF appears to have some protective effect on FVIII. This hypothesis should be tested by a clinical study.